tbuckley/cabot-search huggingface dataset:
Abstract 101: Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma
Authors: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori
Journal: Cancer Research (2023)

Abstract Background &amp; Aim: Intrahepatic cholangiocarcinoma(ICC) accounts for about 5% of all primary liver cancer and is reported to be common in Southeast Asia and parts of Chile, but in recent years it has been increasing in other areas including Europe and the United States. ICC leads to a dismal outcome as the commonly used chemotherapy exhibit purely palliative effects on ICC, enabling only a limited improvement in survival until today. As ICC harbors few actionable target genes with inter-tumor genomic heterogeneity, ICC is considered to be one of the most intractable malignancies of all. Therefore, we implemented the multi-omics analysis especially with comprehension of the oncogenic metabolic changes to confer new treatment strategies. This study aims to unravel the evolution of ICC and identify ICC-specific metabolic pathways and essential targets for eradicating ICC. Approach: We collected 12 primary ICC cases and 77 specimens and conducted a multi-omics approach, including genomics, transcriptomics, proteomics, and metabolomics for each material. Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case indicates a “neutral evolution manner”, regardless of their tumor stage. Upregulation of BCAT1 and BCAT2 might enrich the ‘branched-chain amino acids (BCAA), such as Val, Leu, and Ile degradation pathway’. ICCs cases with the accumulated ubiquitous metabolites, BCAA exhibited poorer prognosis than those cases without BCAA accumulation significantly. Conclusions: Regardless of the inter-tumor heterogeneity in genomic aberrations among ICC cases, we discovered the ubiquitous enrichment of the BCAA metabolic pathway in each tumor. We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions. Citation Format: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 101.
Abstract 5205: B6-<i>KrasLSL-G12C</i> mouse model for assessing the occurrence and development of lung and pancreatic cancer tumors
Authors: Xiaoliu Yang, Yunlong Jiang, Xue Wu, Mingkun Zhang, Jing Zhao, Santi Suryani Chen, Zhiying Li, Erica Trujillo, Mark Wade Moore, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2023)

Abstract In May 2021, the FDA approved sotorasib (Lumakras™) as the first treatment for adult patients with non-small cell lung cancer (NSCLC) harboring the KRASG12C genetic mutation. To study the relationship between the mutational activation of KRAS and tumorigenesis, and promote the development of KRAS-G12C inhibitors, we established the B6-Loxp-Stop-Loxp Kras G12C (B6-KrasLSL-G12C) strain. Upon induction of Cre recombinase, floxed Stop sequences will be deleted in the mouse genome, and the oncogenic KRAS-G12C protein will be expressed at endogenous levels allowing for control of the timing and location of tumor initiation. The C57BL/6-KrasLSL-G12C mice were crossed with the Lyz2-cre mice to develop a spontaneous lung cancer model. KRAS G12C mutant could be detected in type II alveolar epithelial cells (ATII). Furthermore, these mice develop lung cancer at 8-10 weeks of age. In addition, when B6-KrasLSL-G12C mice were crossed with the B6-P53LSL-R172H and Ptf1/p48-Cre mice, the offspring developed pancreatic cancer after 10-12 weeks of tamoxifen treatment. In conclusion, B6-KrasLSL-G12C mice can be used to study the occurrence and development of pancreatic and lung cancer, as well as the potential applications of cancer therapies. Citation Format: Xiaoliu Yang, Yunlong Jiang, Xue Wu, Mingkun Zhang, Jing Zhao, Santi Suryani Chen, Zhiying Li, Erica Trujillo, Mark Wade Moore, Xiang Gao, Cunxiang Ju. B6-KrasLSL-G12C mouse model for assessing the occurrence and development of lung and pancreatic cancer tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5205.
Abstract 666: Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy
Authors: Nithya Gajendran, Maria Gracia Hernandez, Ashutosh Yende, Zubaydah Alahmadi, Xintang Li, Zuleima Munoz, Manasa Suresh, David Quiceno, Karen Tan, Maho Shibata, Satish Noonepalle, Alejandro Villagra
Journal: Cancer Research (2023)

Abstract The cluster of differentiation 47(CD47) is a ubiquitously expressed innate immune checkpoint transmembrane protein but is often overexpressed in cancer cells. CD47 interacts with signal regulatory protein alpha (SIRPα) on macrophages leading to tyrosine phosphatase activation and preventing myosin accumulation at the phagocytic synapse. SIRPa activation triggers the “Do not eat me” signal, negatively regulating phagocytosis in macrophages. Blockade of CD47-SIRPα is a novel immunotherapeutic approach to enhance innate antitumor responses in cancer patients, and clinical data from melanoma patients also showed promising outcomes when CD47 blockade combined with other therapeutic approaches, such as anti-PD-L1. Publications from our lab have provided compelling evidence that histone deacetylase 6 (HDAC6) inhibitors with PD1 blockade delayed tumor progression, enhanced survival, and modulated macrophage phenotype both in vitro and in vivo. The present study aimed to explore the role of HDAC 6 in the CD47/SIRPα axis in phagocytosis and innate antitumor immunity. HDAC inhibition in primary mouse bone marrow-derived macrophages and human THP1 cells enhanced the pro-inflammatory M1 macrophages while downregulating the anti-inflammatory M2 phenotype. In the subsequent studies, we found that HDAC6 inhibition diminished the expression of SIRPα and enhanced the expression of other pro-phagocytic signals, such as Lrp1, CD36, and Mfge8 in macrophages. HDAC6 inhibition also downregulated the CD47 expression in mouse and human melanoma cells. Furthermore, modulation of CD47/SIRPα by HDAC6 inhibitors leads to an increase in phagocytosis in NextA-treated macrophages, further enhanced in CD47-blocking antibodies. We also demonstrated that the combination of systemic administration of the HDAC6 inhibitor Nexturastat A and intertumoral delivery of anti-CD47 reduced SM1 melanoma growth in vivo by increasing immune cell infiltration in the tumor microenvironment. Collectively our results suggest that HDAC6 inhibitors synergize with CD47 blockade to reduce tumor growth and enhance innate antitumor immunity. Citation Format: Nithya Gajendran, Maria Gracia Hernandez, Ashutosh Yende, Zubaydah Alahmadi, Xintang Li, Zuleima Munoz, Manasa Suresh, David Quiceno, Karen Tan, Maho Shibata, Satish Noonepalle, Alejandro Villagra. Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 666.
Abstract 5206: A novel mouse model for preclinical efficacy evaluation of anti-CD3/GPRC5D bispecific antibodies
Authors: Xiaoliu Yang, Xinyuan Liang, Mingkun Zhang, Santi Suryani Chen, Zhiying Li, Erica Trujillo, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2023)

Abstract The FDA has granted Breakthrough Therapy Designation (BTD) for talquetamab, which targets both GPRC5D on multiple myeloma cells and CD3 on T-cells, for treating adult patients with relapsed or refractory multiple myeloma. Results showed that patients who received talquetamab experienced adverse events, including cytokine release syndrome (CRS), neutropenia, skin-related adverse events and dysgeusia. To allow preclinical in vivo evaluation of anti-human CD3/GPRC5D bispecific antibodies, we developed a BALB/c-hCD3EDG mouse model and a human GPRC5D-expressing A20 murine lymphoma cell line. The BALB/c-hCD3EDG cohort (6-8 weeks old) was subcutaneously inoculated with A20-hGPRC5D cells and then treated with anti-CD3/GPRC5D bispecific antibodies. As expected, anti-CD3/GPRC5D bispecific antibody treatment strongly inhibited the growth of A20-hGPRC5D tumors in BALB/c-hCD3EDG mice. To allow a comprehensive safety evaluation of anti-CD3/GPRC5D candidates, including the possibility of CRS and target organ toxicity, we engineered BALB/c-hCD3EDG mice that express hGPRC5D, denoted BALB/c-hCD3EDG/hGPRC5D. Human GPRC5D was detected in the liver, lung, thymus, adipose tissue, and thyroid. In vivo evaluation of anti-CD3/GPRC5D therapy in this mice is currently underway. In conclusion, BALB/c-hCD3EDG/hGPRC5D and BALB/c-hCD3EDG mice bearing A20-hGPRC5D tumors are suitable models for preclinical studies testing anti-CD3/GPRC5D bispecific antibodies. Citation Format: Xiaoliu Yang, Xinyuan Liang, Mingkun Zhang, Santi Suryani Chen, Zhiying Li, Erica Trujillo, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. A novel mouse model for preclinical efficacy evaluation of anti-CD3/GPRC5D bispecific antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5206.
Abstract 4647: Potential of TIMP3 regulating the versican status in the colorectal cancer tumor microenvironment
Authors: Anna Field, Sean Kraus, Kristina Matkowskyj, Dustin Deming, Cheri A. Pasch, Wei Zhang
Journal: Cancer Research (2023)

Abstract Background: In colorectal cancer (CRC), versican (VCAN) accumulation has been found to negatively correlate with CD8+ tumor infiltrating lymphocyte (TIL) abundance and its proteolysis into versikine (Vkine) positively correlates with TIL abundance. TIMP3 has demonstrated the ability to inhibit several ADAMTS proteases able to cleave VCAN to Vkine. Here we investigate the correlation of TIMP3 accumulation in CRCs with the VCAN status and CD8+ T cell infiltration. Methods: Matched primary and metastatic CRC samples from 156 patients who had resected oligometastatic CRC were stained for VCAN, Vkine, TIMP3, and CD8+ TILs. VCAN, Vkine, and TIMP3 were scored using an intensity binning system ranging from 0-3+ and T cells in the epithelium were reported per high power field (HPF). Tumors were designated as high (2 or 3+) or low (0 or 1) for both VCAN and Vkine and positive (+; 1-3) or negative (0) for TIMP3. Tumors designated VCAN low and Vkine high are considered VCAN proteolytic predominant (VPP) and all other combinations are considered VCAN proteolytic weak (VPW). Results: Across the whole dataset, 52% of cancers were VCAN high and 24% were VPP. TIMP3 was detected in 33% of cancers. The frequency of TIMP3 was similar between primary and metastatic tumors (39% and 29%, respectively). Of the VCAN high cancers, 42% were TIMP3+ whereas 61% of the TIMP3+ samples are VCAN high. Of the Vkine high cancers, 44% were TIMP3+ and 36% of VPP cancers were TIMP3+. The prevalence of the VPP phenotype was similar between the TIMP3+ and negative cancers. Additionally, among the TIMP3+ samples 68% were Vkine high versus 46% in TIMP3 negative cancers (p=0.001). VCAN proteolysis correlates with higher CD8+ TIL abundance, thus we assessed the number of CD8+ TILs in TIMP3+ and negative tumors. The TIMP3+ cancers had a median of 2 CD8+ TILs/HPF and the TIMP3 negative cancers has a median of 3 CD8+ TILs/HPF. For VPP cancers, those that were also TIMP3+ had a median of 3 CD8+ TILs/HPF compared to TIMP3 negative cancers which had a median of 6 CD8+ TILs/HPF (p=0.2). Conclusions: TIMP3 correlates with higher levels of VCAN accumulation but does not correlate with lower levels of proteolysis. Future studies are needed to better clarify the impact of TIMP3 and other mediators in regulating VCAN accumulation and proteolysis in the tumor microenvironment. Citation Format: Anna Field, Sean Kraus, Kristina Matkowskyj, Dustin Deming, Cheri A. Pasch, Wei Zhang. Potential of TIMP3 regulating the versican status in the colorectal cancer tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4647.
Abstract 6401: HMGB1 release predicts chemotherapy combinatorial efficacy with TIM-3 blockade
Authors: Alexis Onimus, Jessica Mandula, Paulo Rodriguez, Brian Ruffell
Journal: Cancer Research (2023)

Abstract We have recently shown that TIM-3 blockade promotes response to paclitaxel chemotherapy in preclinical breast cancer models through its ability to suppress uptake of HMGB1-DNA complexes by dendritic cells. However, it remains unclear why paclitaxel is necessary for response to TIM-3 blockade. Here we demonstrate that the taxanes paclitaxel and docetaxel induce the loss of HMGB1 from breast cancer cells in vitro and in vivo. Interestingly, this does not occur through loss of cellular integrity, but rather through an active secretion process involving ADP-ribosylation of HMGB1 by PARP1. PARP1 was activated by docetaxel treatment, as measured by detection of its cleaved form in the cytoplasm, and HMGB1 release was prevented by the use of the PARP inhibitor niraparib. Both PARP1 activation and ADP-ribosylation of HMGB1 were dependent upon the activity of TLR4, a known receptor for paclitaxel, as demonstrated with CRISPR/Cas9-generated knockout cells and TLR4 inhibitors. However, TLR4 stimulation alone was insufficient to induce HMGB1 release. By understanding how taxanes promote the release of HMGB1 we may be able to develop biomarkers for the selection of patients most likely to respond to the combination of chemotherapy and immunotherapy with TIM-3 blocking antibodies. Citation Format: Alexis Onimus, Jessica Mandula, Paulo Rodriguez, Brian Ruffell. HMGB1 release predicts chemotherapy combinatorial efficacy with TIM-3 blockade. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6401.
Abstract 6380: Ultrasensitive detection of circulating human PD-1 and PD-L1 using Single Molecule Counting (SMC) technology
Authors: Laila Faramarzi, Wen-Rong Lie, Rick Wiese, Jared Fiske
Journal: Cancer Research (2023)

Abstract Immune checkpoint proteins are key regulators of the immune system and potential drug targets for cancer immunotherapy. Cancer immunotherapy targeting immune checkpoint, like programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors has shown treatment efficacy for a broad spectrum of human cancers. Immune checkpoint molecules PD-1 and PD-L1 are expressed on the cell surface of immune cells and tumor cells. Recent studies have also reported these immune checkpoint proteins may undergo alternative splicing or proteolytic cleavage to produce soluble checkpoint proteins. Multiple molecular forms of soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) are detectable in patient sera of multiple types of cancer, and these soluble checkpoint proteins have been reported as putative liquid biopsy biomarkers in the diagnosis and prognosis of oncological disease. Though the clinical significance of circulating soluble immune checkpoint protein profiles as predictive biomarkers has yet to be fully explored and validated, we have committed to develop better and more reliable bioassays to further this research. With that, we have developed 2 Luminex-based multiplex immunoassays for simultaneous quantitation of 48 immune checkpoint proteins, including PD-1 and PD-L1, for patient sera and tumor lysate samples. Here we report the development of 2 novel Single Molecule Counting (SMC) technology-based ultrasensitive single-plex immune checkpoint immunoassays for the detection of sPD-L1 and sPD-1 in human serum and plasma samples. Comparative studies demonstrate these SMC ultrasensitive assays possesses at least 10-100-fold higher sensitivity as compared with the Luminex-based immunoassays. Using these novel ultrasensitive assays, we have validated the detection of significant increases in sPD-L1 and sPD-1 in cancer serum samples as compared with the levels in healthy controls. We have also applied these high sensitivity assays to measure human PD-L1 and PD-1 biomarkers in other sample types including urine, tumor lysates and exosomes. In conclusion, we envision that these PD-1 and PD-L1 SMC assays may overcome a major limitation in biomarker utility and enable the ultrasensitive detection of sPD-1 and sPD-L1 in liquid biopsy and blood biomarker research. Citation Format: Laila Faramarzi, Wen-Rong Lie, Rick Wiese, Jared Fiske. Ultrasensitive detection of circulating human PD-1 and PD-L1 using Single Molecule Counting (SMC) technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6380.
Abstract 5496: Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality
Authors: Pamela Luna, Ganesh Acharya, Damieanus Ochola, Swetha Peddibhotla, Chinnadurai Mani, Mark B. Reedy, Komaraiah Palle
Journal: Cancer Research (2023)

Abstract Ovarian cancer (OC) is a highly aggressive disease and the most lethal gynecologic malignancy in women. Although the majority of OC patients respond to chemotherapeutic drugs, more than 70% of the patients relapse and die as a result of chemoresistance. Therefore, novel therapeutics are warranted to prevent chemoresistance and treat the relapsed disease to improve prognosis. Many cancer cells depend on Glutamine as major carbon source and these cells have high Glutaminase (GLS) expression, an enzyme that converts Glutamine to Glutamate. Chemo-resistant OC cells have elevated levels of GLS, which confirms their increased dependency on glutamine metabolism. Based on these observations, we postulated that GLS inhibition may attenuate the aggressive growth of GLS high OC cells and may sensitize to the agents that can further potentiate these effects. Interestingly, GLS inhibition using a clinical-stage drug CB839 caused replication stress and activated DNA damage checkpoint protein 1 (CHK1) mediated cell cycle arrest. These novel findings suggested a role for CHK1 in protecting GLS inhibition-induced DNA damage by facilitating the timely repair of DNA breaks. Based on these observations, we hypothesized that GLS inhibition in combination with CHK1 inhibition may cause synergistic lethality in chemo-resistant and GLShigh OC cells. We evaluated the combination of GLS inhibitor CB839 and CHK1 inhibitor Prexasertib. Our results demonstrate that GLS inhibition-induced CHK1 phosphorylation is significantly attenuated by Prexasertib treatment. Similarly, combined treatment of CB839 and Prexasertib showed significantly elevated levels of DNA damage as measured by COMET assays, replication stress-mediated DNA damage responses, and synergistic OC cell lethality compared to individual drug treatments. Furthermore, CB839 and Prexasertib combination was more synergistic in cells that expressed high GLS compared to low GLS-expressing OC cells indicating the specificity of the combination of these drugs. Together, our studies identified a novel connection between metabolic and DNA damage checkpoint pathways in OC and propose a novel synergistic lethality-based combination therapy to treat chemo-resistant and aggressive OC. Citation Format: Pamela Luna, Ganesh Acharya, Damieanus Ochola, Swetha Peddibhotla, Chinnadurai Mani, Mark B. Reedy, Komaraiah Palle. Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5496.
Abstract 6389: Differential role of CD8 cells and CD4 cells in anti-tumor immunity triggered by tumor cell apoptosis using HSVtk/GCV system
Authors: Sho Umegaki, Hidekazu Shirota, Tomoyuki Iwasaki, Yuki Kasahara, Chikashi Ishioka
Journal: Cancer Research (2023)

Abstract Immune cells can recognize tumor antigens and elicit an adaptive immune response, potentially resulting in tumor regression. Drug-induced dead tumor cells have been reported to enhance anti-tumor immunity, but results are conflicting, possibly due to the immunosuppressive effects of the cytotoxic drugs. To investigate whether apoptotic tumor cells trigger anti-tumor immunity independent of anti-cancer treatment, local immune responses were evaluated after direct induction of tumor cell apoptosis using a herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) system. The inflammatory cytokines IFNγ and IL-12β and anti-inflammatory factor PD-1 and TGFβ1 were upregulated at the tumor site after apoptosis induction. HSV-tk/GCV-induced tumor cell apoptosis resulted in suppression of tumor growth in vivo and promoted the infiltration of CD8 and CD4 T lymphocytes in tumor. To explore the role of T cells after induction of tumor cell death, GCV was administered together with anti-CD8 or anti-CD4 depleting antibodies to syngeneic HSV-tk transfected tumor-bearing mice. CD8 T cell depletion abrogated the anti-tumor efficacy of GCV, indicating that tumor regression was mainly dependent on CD8 T cells. This anti-tumor immunity was enhanced by anti-PD-1 antibody injection. On the contrary, CD4 T cell depletion further inhibited tumor growth than GCV alone, suggesting the potential role of CD4 T cells in suppressive tumor immunity. To elucidate this immunological mechanism, tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion. Foxp3, a regulatory T cell marker, was decreased after CD4 T cell depletion. In addition, Arg1, a marker of immunosuppressive myeloid cells, was significantly downregulated, which was expressed on tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (mMDSCs). Collectively, these findings indicate that tumor cell apoptosis accelerates CD8 T cell-dependent anti-tumor immunity and CD4 T cell-mediated Arg1 production from TAMs and mMDSCs. Citation Format: Sho Umegaki, Hidekazu Shirota, Tomoyuki Iwasaki, Yuki Kasahara, Chikashi Ishioka. Differential role of CD8 cells and CD4 cells in anti-tumor immunity triggered by tumor cell apoptosis using HSVtk/GCV system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6389.